Cytotoxic Activity of LCS-1 is not Only due to Inhibition of SOD1

Abstract

Background The cytotoxic activity of the pyridazin-3-one derivative LCS-1 was previously suggested to be due to the inhibition of superoxide dismutase 1 (SOD1). However, no direct evidence was provided that LCS-1 inhibits SOD1 within cells.

Methods In this study, we investigated the cytotoxic activity of LCS-1 against bloodstream forms of Trypanosoma brucei, a protozoan parasite that does not express copper/zinc-containing SOD1, but an iron-containing superoxide dismutase (FeSOD).

Results At 250 µM, LCS-1 did not inhibit the activity of FeSOD in cell lysates of bloodstream forms of T. brucei, confirming that the compound is a specific inhibitor of SOD1. However, LCS-1 displayed substantial trypanocidal activity with a minimum inhibitory concentration of 10 µM and a half-maximal effective concentration of 1.36 µM, indicating that the cytotoxic action of the compound cannot solely be due to inhibition of SOD1.

Conclusion The results of this study is an important finding as it shows that LCS-1 has more than one cytotoxic mode of action.

Key words

anticancer drugs - drug research - pharmacology

• References

• 1 Somwar R, Shum D, Djaballah H. et al. Identification and preliminary characterization of novel small molecules that inhibit growth of human lung adenocarcinoma cells. J Biomol Screen 2009; 14: 1176-1184
• 2 Somwar R, Erdjument-Bromage H, Larsson E. et al. Superoxide dismutase 1 (SOD1) is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines. Proc Natl Acad Sci USA 2011; 108: 16375-16380
• 3 Kabiri M, Steverding D. Identification of a developmentally regulated iron superoxide dismutase in Trypanosoma brucei. Biochem J 2001; 360: 173-177
• 4 Jackson SMJ, Cooper JB. An analysis of structural similarity in the iron and manganese superoxide dismutases based on known structures and sequences. BioMetals 1998; 11: 159-173
• 5 Steverding D, Kolosevska K, Sánchez-Moreno M. Trypanocidal activity of tetradentated pyridine-based manganese complexes is not linked to inactivation of superoxide dismutase. Exp Parasitol 2018; 192: 1-5
• 6 Steverding D, Scory S. Trypanosoma brucei: Unexpected azide sensitivity of bloodstream forms. J Parasitol 2004; 90: 1188-1190
• 7 Asif M. Various chemical and biological activities of pyridazinone derivatives. Cent Eur J Exp Bio 2017; 5: 1-19
• 8 Suwalsky M, Benites M, Villena F. et al. The organochlorine herbicide chloridazon interacts with cell membranes. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1998; 120: 29-35
• 9 Khan MU, Lem NW, Chandorkar KR. et al. Effects of substituted pyridazinones (San 6706, San 9774, San 9785) on glycerollipids and their associated fatty acids in the leaves of Vicia faba and Hordeum vulgare. Plant Physiol 1979; 64: 300-305
• 10 Papa L, Hahn M, Marsh EL. et al. SOD2 to SOD1 switch in breast cancer. J Biol Chem 2014; 289: 5412-5416